Intensive insulin therapy (IIT) is the use of multiple daily injections (MDIs) of insulin (both long-acting and rapid-acting formulations) or an insulin pump in an effort to mimic the normal secretion of insulin by the pancreas. IIT may also be referred to as physiologic, multiple-component, or basal-bolus insulin therapy. IIT is only one aspect of comprehensive, intensive diabetes therapy to achieve tight glycemic control. IIT is complex because it requires multiple injections or pump boluses per day in addition to routine monitoring and collaborative decision making.

 Frequent self-monitored blood glucose (SMBG) measurements

 Defined and individualized target blood glucose (BG) levels

 Use of SMBG data and glucose patterns to meet treatment goals

 Dose modifications according to the individual’s response to therapy

 Understanding of diet composition, specifically carbohydrate content

 Careful balance of food intake, activity, and insulin dosage

 Use of carbohydrate-to-insulin ratios according to food intake

 Use of correction factors (CFs) for the adjustment of insulin according to glucose levels

 Patient education and motivation, and ongoing interaction between patient and health care team

The Diabetes Control and Complications Trial (DCCT), evaluating patients with recent-onset type 1 diabetes, showed that improved glycemic control (hemoglobin A_1C [HbA_1C] < 7%) significantly reduced rates of microvascular complications, including progression of retinopathy, nephropathy, and neuropathy, but increased rates of hypoglycemia. Intensive insulin therapy was a key part of achieving glycemic control in the DCCT. The Kumamoto Study and the United Kingdom Prospective Diabetes Study (UKPDS) confirmed that improved glycemic control (HbA_1C < 7%) was associated with significantly reduced rates of microvascular complications in patients with recent-onset type 2 diabetes. The long-term extensions of the DCCT and the UKPDS showed significant reductions in cardiovascular complications with good glycemic control and demonstrated that the microvascular benefits of good glycemic control persisted for decades. Later studies in patients with more advanced type 2 diabetes (Action to Control Cardiovascular Risk in Diabetes [ACCORD] trial, Action in Diabetes and Vascular Disease [ADVANCE] trial, and VA Diabetes Trial [VADT]) failed to show that more aggressive glycemic targets (HbA_1C < 6.0%-6.5%) reduced cardiovascular complications, and one study showed an increase in mortality. Rates of hypoglycemia with more aggressive glucose control were significant in all three trials.

All people with diabetes should be considered potential candidates for IIT. However, the degree of therapy intensification must be based on each patient’s personal situation and abilities. Patient characteristics that predict greater success with IIT include motivation, willingness to perform frequent SMBG (up to 6-10 times/day) measurements and record results, time to spend with a diabetes educator, the ability to recognize and treat hypoglycemia, sick day planning, and a supportive network of family or friends. In addition, implementation of IIT requires a cohesive diabetes team that is available for frequent interaction and discussion about results of monitoring, insulin adjustments, and other issues.

Hypoglycemia and weight gain are the most common adverse effects of insulin therapy. IIT in the DCCT resulted in a three-fold increased risk of severe hypoglycemia in comparison with conventional treatment (62 episodes per 100 patient-years of therapy). Since the completion of the DCCT, newer rapid-acting and long-acting insulin analogs have been developed that are associated with less hypoglycemia than the short-acting and intermediate-acting human insulin products used in the trial. Frequent episodes of hypoglycemia can lead to loss of clinical warning symptoms (e.g., palpitations, sweating, hunger) with hypoglycemia (known as hypoglycemia unawareness). A unique risk of pump therapy is diabetic ketoacidosis because pump malfunctions or infusion site problems can interrupt insulin delivery. Finally, IIT requires time and commitment from the patient and may have negative psychosocial and economic implications.

Intensive insulin therapy attempts to mimic normal insulin secretion, which includes continuous basal coverage in addition to bursts of insulin to regulate the rise in glucose after food intake (Fig. 3-1). Basal insulin secretion suppresses hepatic glucose production to control blood glucose levels in the fasting state and premeal periods. Normal basal insulin secretion from the pancreas varies slightly throughout the day, responding to changes in activity, blood glucose levels, and regulatory hormones. Basal coverage is usually accomplished with injections of long-acting insulin preparations or with the basal infusion function on the insulin pump. Bolus insulin doses consist of two components, the nutritional dose (the amount of insulin required to manage glucose excursions following meals) and the correction dose (the amount of insulin required to reduce a high glucose level detected before a meal). Bolus coverage is accomplished by injections of rapid-acting or short-acting insulin preparations or with use of the bolus function on the insulin pump. Physiologic insulin secretion requirements are approximately 50% basal and 50% bolus.

A long-acting insulin is injected either once or twice daily to provide the basal insulin portion of an MDI regimen, which is approximately 50% of a patient’s total daily dose. Ideally, basal insulin should cover background insulin needs only, independent of food intake. A rapid-acting or short-acting insulin is injected before meals to provide the bolus insulin portion of an MDI regimen (see Fig. 3-1). Rapid-acting insulin is preferred because of the rapid onset and short duration of action. A patient can adjust each bolus dose to match the carbohydrate intake and to correct for high glucose levels before the meal, whereas the basal dose remains constant from day to day. Premixed “biphasic” insulin preparations combine either a rapid-acting insulin analog or regular human insulin with a crystalline protaminated form of the analog or NPH (neutral protamine Hagedorn) human insulin in an attempt to imitate basal and bolus therapies with fewer injections.

See Table 3-1.

See Table 3-1.

 Five to 10 minutes before meals and snacks when BG is in the normal range (70-130 mg/dL)

 Fifteen to 30 minutes before meals if the premeal BG is higher than 130 mg/dL (Correctional bolus insulin [CF] is added to meal insulin when the BG is elevated.)

 Immediately after eating, if gastroparesis or an intercurrent illness is present

 Upon arrival of food, if the patient is unfamiliar with meal size, content, or timing (i.e., in a restaurant or hospital)

 Insulin glargine or detemir should be taken at bedtime if a dawn phenomenon is present or at any consistent time, approximately every 24 hours. (Insulin glargine or detemir cannot be mixed with other insulins.)

 If nocturnal hypoglycemia results from taking a full dose of glargine or detemir at bedtime, an option would be to split the dose so that 50% is taken in the morning and the other 50% is taken in the evening, approximately 12 hours apart.

 NPH insulin is given in the morning and at bedtime to avoid nocturnal hypoglycemia.

An insulin pump is a small, lightweight, portable, battery-operated device that is either attached directly to the body (patch pump) or worn on clothing or a belt like a pager (traditional pump). A traditional pump is composed of a pump reservoir (which holds a 2- to 3-day supply of rapid-acting or short-acting insulin) connected to an infusion set, which ends in a cannula that is inserted into the skin and changed every 2 to 3 days. A patch pump is tubing free and consists of a disposal reservoir that attaches directly to the body with self-adhesive backing and a built-in infusion set in the device for insertion into the subcutaneous tissue. The patch pump is controlled by a handheld personal digital assistant. Insulin is delivered through either system in microliter amounts continuously over 24 hours. The user is responsible for setting basal rates and determining bolus doses, depending on the meal ingested and the SMBG results. Currently, six companies offer insulin pumps in the United States; several other pumps are in development. Each pump has special features and functions that are unique and help with the flexibility of pump use. To learn more about each of these pumps, contact the companies listed in Table 3-2.

 Commit at least 2 to 3 months to pump initiation, including multiple meetings with the diabetes team before, during, and after the pump is initiated.

 Demonstrate the ability to monitor BG values at least 4 to 10 times per day; keep logs of BG readings, insulin doses, and food consumed; and communicate information to the team.

 Review pump training materials and practice pump functions at least 2 or 3 times before wearing the pump.

 Be willing to test basal rates or agree to wear a continuous glucose monitoring (CGM) system or device to ensure that basal rates are set appropriately.